Journal
JOURNAL OF MEDICINAL CHEMISTRY
Volume 49, Issue 6, Pages 1867-1873Publisher
AMER CHEMICAL SOC
DOI: 10.1021/jm051273d
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Funding
- NIGMS NIH HHS [R01 GM059791-06, R01 GM059791, GM59791] Funding Source: Medline
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Type 4 phosphodiesterase (PDE4) inhibitors are emerging as new treatments for a number of disorders including asthma and chronic obstructive pulmonary disease. Here we report the biochemical characterization on the second generation inhibitor (+)-1 (L-869298, IC50 = 0.4 nM) and its enantiomer (-)-1 (L-869299, IC50 = 43 nM) and their cocrystal structures with PDE4D at 2.0 angstrom resolution. Despite the 107-fold affinity difference, both enantiomers interact with the same sets of residues in the rigid active site. The weaker (-)-1 adopts an unfavorable conformation to preserve the pivotal interactions between the Mg-bound waters and the N-oxide of pyridine. These structures support a model in which inhibitors are anchored by the invariant glutamine at one end and the metal-pocket residues at another end. This model provides explanations for most of the observed structure-activity relationship and the metal ion dependency of the catechol-ether based inhibitors and should facilitate their further design.
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